Involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like Behaviors
Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood, and its treatment is unsatisfactory. Na<sup>+</sup>, K<sup>+</sup>-ATPase is a ma...
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2024-01-01
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| author | Noa Horesh Ilana Pelov Ilana Pogodin Hiba Zannadeh Haim Rosen Anastasiia Leonidovna Mikhrina Moran Dvela-Levitt Vishnu Priya Sampath David Lichtstein |
| author_facet | Noa Horesh Ilana Pelov Ilana Pogodin Hiba Zannadeh Haim Rosen Anastasiia Leonidovna Mikhrina Moran Dvela-Levitt Vishnu Priya Sampath David Lichtstein |
| author_sort | Noa Horesh |
| collection | DOAJ |
| description | Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood, and its treatment is unsatisfactory. Na<sup>+</sup>, K<sup>+</sup>-ATPase is a major plasma membrane transporter and signal transducer. The catalytic α subunit of this enzyme is the binding site for cardiac steroids. Three α isoforms of the Na<sup>+</sup>, K<sup>+</sup>-ATPase are present in the brain. Previous studies have supported the involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase and endogenous cardiac steroids (ECS) in the etiology of BD. Decreased brain ECS has been found to elicit anti-manic and anti-depressive-like behaviors in mice and rats. However, the identity of the specific α isoform involved in these behavioral effects is unknown. Here, we demonstrated that decreasing ECS through intracerebroventricular (i.c.v.) administration of anti-ouabain antibodies (anti-Ou-Ab) decreased the activity of α1<sup>+/−</sup> mice in forced swimming tests but did not change the activity in wild type (wt) mice. This treatment also affected exploratory and anxiety behaviors in α1<sup>+/−</sup> but not wt mice, as measured in open field tests. The i.c.v. administration of anti-Ou-Ab decreased brain ECS and increased brain Na<sup>+</sup>, K<sup>+</sup>-ATPase activity in wt and α1<sup>+/−</sup> mice. The serum ECS was lower in α1<sup>+/−</sup> than wt mice. In addition, a study in human participants demonstrated that serum ECS significantly decreased after treatment. These results suggest that the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 isoform is involved in depressive- and manic-like behaviors and support that the Na<sup>+</sup>, K<sup>+</sup>-ATPase/ECS system participates in the etiology of BD. |
| first_indexed | 2024-03-08T03:55:53Z |
| format | Article |
| id | doaj.art-b5bba9b3296f49f89f368eb3334a8cf9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T03:55:53Z |
| publishDate | 2024-01-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b5bba9b3296f49f89f368eb3334a8cf92024-02-09T15:14:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-01-01253164410.3390/ijms25031644Involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like BehaviorsNoa Horesh0Ilana Pelov1Ilana Pogodin2Hiba Zannadeh3Haim Rosen4Anastasiia Leonidovna Mikhrina5Moran Dvela-Levitt6Vishnu Priya Sampath7David Lichtstein8Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91905, IsraelJerusalem Mental Health Center, Eitanim Psychiatric Hospital, Jerusalem 91060, IsraelDepartment of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91905, IsraelDepartment of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91905, IsraelDepartment of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91905, IsraelDepartment of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91905, IsraelThe Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, IsraelDepartment of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91905, IsraelDepartment of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91905, IsraelBipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood, and its treatment is unsatisfactory. Na<sup>+</sup>, K<sup>+</sup>-ATPase is a major plasma membrane transporter and signal transducer. The catalytic α subunit of this enzyme is the binding site for cardiac steroids. Three α isoforms of the Na<sup>+</sup>, K<sup>+</sup>-ATPase are present in the brain. Previous studies have supported the involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase and endogenous cardiac steroids (ECS) in the etiology of BD. Decreased brain ECS has been found to elicit anti-manic and anti-depressive-like behaviors in mice and rats. However, the identity of the specific α isoform involved in these behavioral effects is unknown. Here, we demonstrated that decreasing ECS through intracerebroventricular (i.c.v.) administration of anti-ouabain antibodies (anti-Ou-Ab) decreased the activity of α1<sup>+/−</sup> mice in forced swimming tests but did not change the activity in wild type (wt) mice. This treatment also affected exploratory and anxiety behaviors in α1<sup>+/−</sup> but not wt mice, as measured in open field tests. The i.c.v. administration of anti-Ou-Ab decreased brain ECS and increased brain Na<sup>+</sup>, K<sup>+</sup>-ATPase activity in wt and α1<sup>+/−</sup> mice. The serum ECS was lower in α1<sup>+/−</sup> than wt mice. In addition, a study in human participants demonstrated that serum ECS significantly decreased after treatment. These results suggest that the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 isoform is involved in depressive- and manic-like behaviors and support that the Na<sup>+</sup>, K<sup>+</sup>-ATPase/ECS system participates in the etiology of BD.https://www.mdpi.com/1422-0067/25/3/1644bipolar disorderNa<sup>+</sup>, K<sup>+</sup>-ATPaseα isoformintracellular signalingendogenous cardiac steroidsforced swimming test |
| spellingShingle | Noa Horesh Ilana Pelov Ilana Pogodin Hiba Zannadeh Haim Rosen Anastasiia Leonidovna Mikhrina Moran Dvela-Levitt Vishnu Priya Sampath David Lichtstein Involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like Behaviors International Journal of Molecular Sciences bipolar disorder Na<sup>+</sup>, K<sup>+</sup>-ATPase α isoform intracellular signaling endogenous cardiac steroids forced swimming test |
| title | Involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like Behaviors |
| title_full | Involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like Behaviors |
| title_fullStr | Involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like Behaviors |
| title_full_unstemmed | Involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like Behaviors |
| title_short | Involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like Behaviors |
| title_sort | involvement of the na sup sup k sup sup atpase α1 isoform and endogenous cardiac steroids in depression and manic like behaviors |
| topic | bipolar disorder Na<sup>+</sup>, K<sup>+</sup>-ATPase α isoform intracellular signaling endogenous cardiac steroids forced swimming test |
| url | https://www.mdpi.com/1422-0067/25/3/1644 |
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